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NMD Complexes: Eukaryotic mRNA Quality Control

Objective

Nonsense-mediated mRNA decay (NMD) is an essential mechanism controlling translation in the eukaryotic cell. NMD ascertains accurate expression of the genetic information by quality controlling messenger RNA (mRNA). During translation, NMD factors recognize and target to degradation aberrant mRNAs that have a premature stop codon (PTC) and that would otherwise lead to the production of truncated proteins which could be harmful for the cell. A wide range of genetic diseases have their origin in the mechanisms of NMD. Discrimination of a PTC from a correct termination codon depends on splicing and translation, and it is the first and foremost step in human NMD. The molecular mechanism of this process remains elusive to date.
In the research proposed, I will undertake to elucidate the molecular basis of translation termination and induction of NMD. I will study complexes involved in human translation termination at a normal stop codon and involved in NMD. I will employ an array of innovative techniques including recombinant production of human protein complexes by the MultiBac system, mammalian in vitro translation, mass spectrometry for detecting relevant protein modifications, biophysical techniques, mutational analyses and RNA-interference experiments. Stable ribosomal complexes with termination factors and complexes of NMD factors will be used for structure determination by cryo-electron microscopy. State-of-the-art image processing will be applied to address the inherent heterogeneity of the complexes. Hybrid approaches will allow the combination of cryo-EM structures with existing high-resolution structures of factors involved for generation of quasi-atomic models thereby visualizing molecular mechanisms of NMD action. This interdisciplinary work will foster our understanding at a molecular level of a paramount step in mRNA quality control, which is a vital prerequisite for the development of new treatment strategies in NMD-related diseases.

Call for proposal

ERC-2011-StG_20101109
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Host institution

EUROPEAN MOLECULAR BIOLOGY LABORATORY
Address
Meyerhofstrasse 1
69117 Heidelberg
Germany
Activity type
Research Organisations
EU contribution
€ 1 176 825
Principal investigator
Christiane Helene Berger-Schaffitzel (Dr.)
Administrative Contact
Danielle Desravines (Dr.)

Beneficiaries (1)

EUROPEAN MOLECULAR BIOLOGY LABORATORY
Germany
EU contribution
€ 1 176 825
Address
Meyerhofstrasse 1
69117 Heidelberg
Activity type
Research Organisations
Principal investigator
Christiane Helene Berger-Schaffitzel (Dr.)
Administrative Contact
Danielle Desravines (Dr.)